Non-steroidal anti-inflammatory drugs as a targeted therapy for bone marrow failure in Ghosal Hematodiaphyseal Dysplasia.

Advances in genomic diagnostics hold promise for improved care of rare hematologic diseases. Here we describe a novel targeted therapeutic approach for Ghosal hematodiaphyseal dysplasia, an autosomal recessive disease characterized by severe normocytic anemia and bone abnormalities due to loss-of-function mutations in Thromboxane A Synthase 1 (TBXAS1). TBXAS1 metabolizes prostaglandin (PG)H2, the cyclooxygenase (COX) product of arachidonic acid, into thromboxane A2. Loss-of-function in TBXAS results in an increase in PGH2 availability for other PG synthases. Current treatment for Ghosal syndrome consists of corticosteroids. We hypothesized that non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-1 and COX-2, could ameliorate the effects of TBXAS1 loss and improve hematologic function by reducing prostaglandin formation. We treated two patients with Ghosal syndrome, one adult and one pediatric, with standard doses of NSAIDs (aspirin or ibuprofen). Both patients had rapid improvement of hematologic parameters and inflammatory markers without adverse events. Mass spectrometry analysis demonstrated that urinary PG metabolites were increased along with proinflammatory lipoxygenase (LOX) products 5-Hydroxyeicosatetraenoic acid and leukotriene E4. Our data show that NSAIDs at standard doses surprisingly reduced both COX and LOX products, leading to the resolution of cytopenias, and should be considered for first-line treatment for Ghosal syndrome.